Adenosine A2 receptor stimulation protects the predamaged liver from cold preservation through activation of cyclic adenosine monophosphate-protein kinase A pathway

The shortage of organ donors has led to reconsideration for the use of non- heart-beating donors (NHBDs), However, graft injury caused by warm ischemia in livers From NHBDs strongly affects posttransplantation outcome, The aim of the present study is to investigate the role of adenosine A2 receptor w ith regard to hepatic viability after cold preservation of NHBD livers. Car diac arrest was induced in Wistar rats by phrenotomy of the anesthetized no nheparinized animal. After 60 minutes, the livers were excised and flushed with 60 mi, of histidine-tryptophan-ketoglutarate (HTK) and stored submerge d in HTK at 4 degrees C for 24. hours. Reperfusion was performed in vitro a fter all livers were incubated at 22 degrees C in saline solution to accoun t for the period of slow rewarming during surgical implantation in vivo. Ad dition of the selective A2-receptor agonist (CGS 21680; 30 mu g/ 100 mL) to the preservation solution resulted in a significant reduction to one quart er of the parenchymal enzyme release of alanine aminotransferase or lactate dehydrogenase on reperfusion and promoted a 2-fold increase in hepatic bil e production. This salutory effect was accompanied by a significant increas e (40%) in the activity ratio of protein kinase A (PKA) in the liver tissue and could be abrogated in large part by the PKA inhibitor, Rp-cAMPs, Stimu lation of the adenosine A2 receptor during harvest and storage of the graft improves maintenance of tissue integrity in liver grafts, A major part of this effect, which may represent a promising approach for the use of NHBD g rafts, seems to be mediated through activation of PKA Copyright (C) 2000 by the American Association for the Study of Liver Diseases.